S. aureus is a major human pathogen of the respiratory tract that activates the type I & III interferon (IFN) cascades. Influenza virus also activates a significant IFN response and significantly increases the susceptibility to secondary S. aureus infection in the lung. Although much is known about the role of IFNs and influenza co-infection in the lung, much less is known about the role of influenza infection and the role the host response plays to S. aureus colonization of the upper airway. Bacteria aspirated from the upper respiratory tract leads to pneumonia and activation of IFN signaling in the lung, contributing to infection and pulmonary pathology. In the experiments proposed we will establish the role of IFN signaling in colonization (bacterial burden in the nasopharynx) of S. aureus in the upper respiratory tract and the influence of influenza infection on colonization, investigating bot the microbial and host factors involved. We will determine the effect IFN signaling has on immune cell function and the ability of influenza neuraminidase to provide an environment conducive to colonization. This work will be accomplished using wild-type and knockout mice in murine models of nasal colonization and acute pneumonia. S. aureus targets human immune cells, therefore pathology due to immune cell recruitment and function will be documented in a novel humanized mouse model of S. aureus infection. In the context of influenza we will address two questions: does influenza increase susceptibility to colonization, and in already colonized hosts does influenza cause increased bacterial burden and secondary pneumonia. We will complement in vivo studies with in vitro tissue culture, adherence and biofilm assays. We will also test approved drugs in an attempt to reduce levels of S. aureus colonization. Given the limited efficacy of currently available antibiotics in the setting of MRSA infection, these studies have potential applications for immunomodulary therapy and decolonization strategies to reduce infection rates and vastly improve patient outcome.